Where pesticides are involved, the chemicals that figure most prominently in the case histories are DDT, lindane, benzene hexachloride, the nitrophenols, the common moth crystal paradichlorobenzene, chlordane, and, of course, the solvents in which they are carried. As this physician emphasizes, pure exposure to a single chemical is the exception, rather than the rule. The commercial product usually contains combinations of several chemicals, suspended in a petroleum distillate plus some dispersing agent. The aromatic cyclic and unsaturated hydrocarbons of the vehicle may themselves be a major factor in the damage done the blood-forming organs. From the practical rather than the medical standpoint this distinction is of little importance, however, because these petroleum solvents are an inseparable part of most common spraying practices.
The medical literature of this and other countries contains many significant cases that support Dr. Hargraves' belief in a cause-and-effect relation between these chemicals and leukemia and other blood disorders. They concern such everyday people as farmers caught in the "fallout" of their own spray rigs or of planes, a college student who sprayed his study for ants and remained in the room to study, a woman who had installed a portable lindane vaporizer in her home, a worker in a cotton field that had been sprayed with chlordane and toxaphene. They carry, half concealed within their medical terminology, stories of such human tragedies as that of two young cousins in Czechoslovakia, boys who lived in the same town and had always worked and played together. Their last and most fateful employment was at a farm cooperative where it was their job to unload sacks of an insecticide (benzene hexachloride). Eight months later one of the boys was stricken with acute leukemia. In nine days he was dead. At about this time his cousin began to tire easily and to run a temperature. Within about three months his symptoms became more severe and he, too, was hospitalized. Again the diagnosis was acute leukemia, and again the disease ran its inevitably fatal course.
And then there is the case of a Swedish farmer, strangely reminiscent of that of the Japanese fisherman Kuboyama of the tuna vessel the Lucky Dragon. Like Kuboyama, the farmer had been a healthy man, gleaning his living from the land as Kuboyama had taken his from the sea. For each man a poison drifting out of the sky carried a death sentence. For one, it was radiation-poisoned ash; for the other, chemical dust. The farmer had treated about 60 acres of land with a dust containing DDT and benzene hexachloride. As he worked puffs of wind brought little clouds of dust swirling about him. "In the evening he felt unusually tired, and during the subsequent days he had a general feeling of weakness, with backache and aching legs as well as chills, and was obliged to take to his bed," says a report from the Medical Clinic at Lund. "His condition became worse, however, and on May 19 [a week after the spraying] he applied for admission to the local hospital." He had a high fever and his blood count was abnormal. He was transferred to the Medical Clinic, where, after an illness of two and one half months, he died. A post-mortem examination revealed a complete wasting away of the bone marrow.
How a normal and necessary process such as cell division can become altered so that it is alien and destructive is a problem that has engaged the attention of countless scientists and untold sums of money. What happens in a cell to change its orderly multiplication into the wild and uncontrolled proliferation of cancer?
When answers are found they will almost certainly be multiple. Just as cancer itself is a disease that wears many guises, appearing in various forms that differ in their origin, in the course of their development, and in the factors that influence their growth or regression, so there must be a corresponding variety of causes. Yet underlying them all, perhaps, only a few basic kinds of injuries to the cell are responsible. Here and there, in research widely scattered and sometimes not undertaken as a cancer study at all, we see glimmerings of the first light that may one day illuminate this problem.
Again we find that only by looking at some of the smallest units of life, the cell and its chromosomes, can we find that wider vision needed to penetrate such mysteries. Here, in this microcosm, we must look for those factors that somehow shift the marvelously functioning mechanisms of the cell out of their normal patterns.
One of the most impressive theories of the origin of cancer cells was developed by a German biochemist, Professor Otto Warburg of the Max Planck Institute of Cell Physiology. Warburg has devoted a lifetime of study to the complex processes of oxidation within the cell. Out of this broad background of understanding came a fascinating and lucid explanation of the way a normal cell can become malignant.
Warburg believes that either radiation or a chemical carcinogen acts by destroying the respiration of normal cells, thus depriving them of energy. This action may result from minute doses often repeated. The effect, once achieved, is irreversible. The cells not killed outright by the impact of such a respiratory poison struggle to compensate for the loss of energy. They can no longer carry on that extraordinary and efficient cycle by which vast amounts of ATP are produced, but are thrown back on a primitive and far less efficient method, that of fermentation. The struggle to survive by fermentation continues for a long period of time. It continues through ensuing cell divisions, so that all the descendant cells have this abnormal method of respiration. Once a cell has lost its normal respiration it cannot regain it—not in a year, not in a decade or in many decades. But little by little, in this grueling struggle to restore lost energy, those cells that survive begin to compensate by increased fermentation. It is a Darwinian struggle, in which only the most fit or adaptable survive. At last they reach the point where fermentation is able to produce as much energy as respiration. At this point, cancer cells may be said to have been created from normal body cells.
Warburg's theory explains many otherwise puzzling things. The long latent period of most cancers is the time required for the infinite number of cell divisions during which fermentation is gradually increasing after the initial damage to respiration. The time required for fermentation to become dominant varies in different species because of different fermentation rates: a short time in the rat, in which cancers appear quickly, a long time (decades even) in man, in whom the development of malignancy is a deliberate process.
The Warburg theory also explains why repeated small doses of a carcinogen are more dangerous under some circumstances than a single large dose. The latter may kill the cells outright, whereas the small doses allow some to survive, though in a damaged condition. These survivors may then develop into cancer cells. This is why there is no "safe" dose of a carcinogen.
In Warburg's theory we also find explanation of an otherwise incomprehensible fact—that one and the same agent can be useful in treating cancer and can also cause it. This, as everyone knows, is true of radiation, which kills cancer cells but may also cause cancer. It is also true of many of the chemicals now used against cancer. Why? Both types of agents damage respiration. Cancer cells already have a defective respiration, so with additional damage they die. The normal cells, suffering respiratory damage for the first time, are not killed but are set on the path that may eventually lead to malignancy.
Warburg's ideas received confirmation in 1953 when other workers were able to turn normal cells into cancer cells merely by depriving them of oxygen intermittently over long periods. Then in 1961 other confirmation came, this time from living animals rather than tissue cultures. Radioactive tracer substances were injected into cancerous mice. Then by careful measurements of their respiration, it was found that the fermentation rate was markedly above normal, just as Warburg had foreseen.
Measured by the standards established by Warburg, most pesticides meet the criterion of the perfect carcinogen too well for comfort. As we have seen in the preceding chapter, many of the chlorinated hydrocarbons, the phenols, and some herbicides interfere with oxidation and energy production within the cell. By these means they may be creating sleeping cancer cells, cells in which an irreversible malignancy will slumber long and undetected until finally—its cause long forgotten and
even unsuspected—it flares into the open as recognizable cancer.
Another path to cancer may be by way of the chromosomes. Many of the most distinguished research men in this field look with suspicion on any agent that damages the chromosomes, interferes with cell division, or causes mutations. In the view of these men any mutation is a potential cause of cancer. Although discussions of mutations usually refer to those in the germ cells, which may then make their effect felt in future generations, there may also be mutations in the body cells. According to the mutation theory of the origin of cancer, a cell, perhaps under the influence of radiation or of a chemical, develops a mutation that allows it to escape the controls the body normally asserts over cell division. It is therefore able to multiply in a wild and unregulated manner. The new cells resulting from these divisions have the same ability to escape control, and in time enough such cells have accumulated to constitute a cancer.
Other investigators point to the fact that the chromosomes in cancer tissue are unstable; they tend to be broken or damaged, the number may be erratic, there may even be double sets.
The first investigators to trace chromosome abnormalities all the way to actual malignancy were Albert Levan and John J. Biesele, working at the Sloan-Kettering Institute in New York. As to which came first, the malignancy or the disturbance of the chromosomes, these workers say without hesitation that "the chromosomal irregularities precede the malignancy." Perhaps, they speculate, after the initial chromosome damage and the resulting instability there is a long period of trial and error through many cell generations (the long latent period of malignancy) during which a collection of mutations is finally accumulated which allow the cells to escape from control and embark on the unregulated multiplication that is cancer.
Ojvind Winge, one of the early proponents of the theory of chromosome instability, felt that chromosome doublings were especially significant. Is it coincidence, then, that benzene hexachloride and its relative, lindane, are known through repeated observations to double the chromosomes in experimental plants—and that these same chemicals have been implicated in many well-documented cases of fatal anemias? And what of the many other pesticides that interfere with cell division, break chromosomes, cause mutations?
It is easy to see why leukemia should be one of the most common diseases to result from exposure to radiation or to chemicals that imitate radiation. The principal targets of physical or chemical mutagenic agents are cells that are undergoing especially active division. This includes various tissues but most importantly those engaged in the production of blood. The bone marrow is the chief producer of red blood cells throughout life, sending some 10 million new cells per second into the bloodstream of man. White corpuscles are formed in the lymph glands and in some of the marrow cells at a variable, but still prodigious, rate.
Certain chemicals, again reminding us of radiation products like Strontium 90, have a peculiar affinity for the bone marrow. Benzene, a frequent constituent of insecticidal solvents, lodges in the marrow and remains deposited there for periods known to be as long as 20 months. Benzene itself has been recognized in medical literature for many years as a cause of leukemia.
The rapidly growing tissues of a child would also afford conditions most suitable for the development of malignant cells. Sir Macfarlane Burnet has pointed out that not only is leukemia increasing throughout the world but it has become most common in the three- to four-year age bracket, an age incidence shown by no other disease. According to this authority, "The peak between three and four years of age can hardly have any other interpretation than exposure of the young organism to a mutagenic stimulus around the time of birth."
Another mutagen known to produce cancer is urethane. When pregnant mice are treated with this chemical not only do they develop cancer of the lung but their young do, also. The only exposure of the infant mice to urethane was prenatal in these experiments, proving that the chemical must have passed through the placenta. In human populations exposed to urethane or related chemicals there is a possibility that tumors will develop in infants through prenatal exposure, as Dr. Hueper has warned.
Urethane as a carbamate is chemically related to the herbicides IPC and CIPC. Despite the warnings of cancer experts, carbamates are now widely used, not only as insecticides, weed killers, and fungicides, but also in a variety of products including plasticizers, medicines, clothing, and insulating materials.
The road to cancer may also be an indirect one. A substance that is not a carcinogen in the ordinary sense may disturb the normal functioning of some part of the body in such a way that malignancy results. Important examples are the cancers, especially of the reproductive system, that appear to be linked with disturbances of the balance of sex hormones; these disturbances, in turn, may in some cases be the result of something that affects the ability of the liver to preserve a proper level of these hormones. The chlorinated hydrocarbons are precisely the kind of agent that can bring about this kind of indirect carcinogenesis, because all of them are toxic in some degree to the liver.
The sex hormones are, of course, normally present in the body and perform a necessary growth-stimulating function in relation to the various organs of reproduction. But the body has a built-in protection against excessive accumulations, for the liver acts to keep a proper balance between male and female hormones (both are produced in the bodies of both sexes, although in different amounts) and to prevent an excess accumulation of either. It cannot do so, however, if it has been damaged by disease or chemicals, or if the supply of the B-complex vitamins has been reduced. Under these conditions the estrogens build up to abnormally high levels.
What are the effects? In animals, at least, there is abundant evidence from experiments. In one such, an investigator at the Rockefeller Institute for Medical Research found that rabbits with livers damaged by disease show a very high incidence of uterine tumors, thought to have developed because the liver was no longer able to inactivate the estrogens in the blood, so that they "subsequently rose to a carcinogenic level." Extensive experiments on mice, rats, guinea pigs, and monkeys show that prolonged administration of estrogens (not necessarily at high levels) has caused changes in the tissues of the reproductive organs, "varying from benign overgrowths to definite malignancy." Tumors of the kidneys have been induced in hamsters by administering estrogens.
Although medical opinion is divided on the question, much evidence exists to support the view that similar effects may occur in human tissues. Investigators at the Royal Victoria Hospital at McGill University found two thirds of 150 cases of uterine cancer studied by them gave evidence of abnormally high estrogen levels. In 90 per cent of a later series of 20 cases there was similar high estrogen activity.
It is possible to have liver damage sufficient to interfere with estrogen elimination without detection of the damage by any tests now available to the medical profession. This can easily be caused by the chlorinated hydrocarbons, which, as we have seen, set up changes in liver cells at very low levels of intake. They also cause loss of the B vitamins. This, too, is extremely important, for other chains of evidence show the protective role of these vitamins against cancer. The late C. P. Rhoads, onetime director of the Sloan-Kettering Institute for Cancer Research, found that test animals exposed to a very potent chemical carcinogen developed no cancer if they had been fed yeast, a rich source of the natural B vitamins. A deficiency of these vitamins has been found to accompany mouth cancer and perhaps cancer of other sites in the digestive tract. This has been observed not only in the United States but in the far northern parts of Sweden and Finland, where the diet is ordinarily deficient in vitamins. Groups prone to primary liver cancer, as for example the Bantu tribes of Africa, are typically subject to malnutrition. Cancer of the male breast is also prevalent in parts of Africa, associated with liver disease and malnutrition. In postwar Greece enlargement of the male breast was a common accompaniment of periods of starvation.
In brief, the argument for the indirect role of pes
ticides in cancer is based on their proven ability to damage the liver and to reduce the supply of B vitamins, thus leading to an increase in the "endogenous" estrogens, or those produced by the body itself. Added to these are the wide variety of synthetic estrogens to which we are increasingly exposed—those in cosmetics, drugs, foods, and occupational exposures. The combined effect is a matter that warrants the most serious concern.
Human exposures to cancer-producing chemicals (including pesticides) are uncontrolled and they are multiple. An individual may have many different exposures to the same chemical. Arsenic is an example. It exists in the environment of every individual in many different guises: as an air pollutant, a contaminant of water, a pesticide residue on food, in medicines, cosmetics, wood preservatives, or as a coloring agent in paints and inks. It is quite possible that no one of these exposures alone would be sufficient to precipitate malignancy—yet any single supposedly "safe dose" may be enough to tip the scales that are already loaded with other "safe doses."
Or again the harm may be done by two or more different carcinogens acting together, so that there is a summation of their effects. The individual exposed to DDT, for example, is almost certain to be exposed to other liver-damaging hydrocarbons, which are so widely used as solvents, paint removers, degreasing agents, dry-cleaning fluids, and anesthetics. What then can be a "safe dose" of DDT?
The situation is made even more complicated by the fact that one chemical may act on another to alter its effect. Cancer may sometimes require the complementary action of two chemicals, one of which sensitizes the cell or tissue so that it may later, under the action of another or promoting agent, develop true malignancy. Thus, the herbicides IPC and CIPC may act as initiators in the production of skin tumors, sowing the seeds of malignancy that may be brought into actual being by something else—perhaps a common detergent.
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